Glycopyrronium bromide is a long acting anti-muscarinic agent currently under development for the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD). See for example, WO01/76575.
Part of the development of glycopyrronium bromide involves milling of the active substance down to a particle size suitable for use in a dry powder inhalation formulation. During the course of formulation development it has been found that small pockets of amorphous glycopyrronium bromide formed on the surface of milled particles lead to substantial agglomeration and fusion of these particles, creating larger particles that are unsuitable for inhaled delivery. Characterisation of the amorphous form of glycopyrronium bromide reveals that the solid is highly hygroscopic. This material becomes sticky upon sorption of moisture at low relative humidity (RH), and then finally crystallises to a non-hygoscopic hard crystalline substance.
The glass transition temperature (Tg) of amorphous glycopyrronium bromide, as determined by differential scanning calorimetry (DSC), is relatively low at 64.9° C. Moisture adsorbed by the amorphous material acts as a plasticizer, lowering the glass transition temperature to ambient temperature at low RH. Clearly, milled substance which contains part amorphous and part crystalline material is not in a stable physical form at ambient temperature and low RH. This complexity means that it is difficult to achieve batch-to-batch consistency in the milling process, resulting in formulations with variable performance when applied to a dry powder inhaler (DPI).